Frequent chromatin rearrangements in myelodysplastic syndromes--what stands behind?

Myelodysplastic syndromes (MDS) represent a clinically and genetically heterogeneous group of clonal haematopoietic diseases characterized by a short survival and high rate of transformation to acute myeloid leukaemia (AML). In spite of this variability, MDS is associated with typical recurrent non-random cytogenetic defects. Chromosomal abnormalities are detected in the malignant bone-marrow cells of approximately 40-80 % of patients with primary or secondary MDS. The most frequent chromosomal rearrangements involve chromosomes 5, 7 and 8. MDS often shows presence of unbalanced chromosomal changes, especially large deletions [del(5), del(7q), del(12p), del(18q), del(20q)] or losses of whole chromosomes (7 and Y). The most typical cytogenetic abnormality is a partial or complete deletion of 5q- that occurs in roughly 30 % of all MDS cases either as the sole abnormality or in combination with other aberrations as a part of frequently complex karyotypes. The mechanisms responsible for the formation of MDS-associated recurrent translocations and complex karyotypes are unknown. Since some of the mentioned aberrations are characteristic for several haematological malignancies, more general cellular conditions could be expected to play a role. In this article, we introduce the most common rearrangements linked to MDS and discuss the potential role of the non-random higher-order chromatin structure in their formation. A contribution of the chromothripsis - a catastrophic event discovered only recently - is considered to explain how complex karyotypes may occur (during a single event).

Karyotype, centric fusion polymorphism and chromosomal aberrations in captive-born mountain reedbuck (Redunca fulvorufula).

Chromosomes of fourteen captive-born mountain reedbucks (Redunca fulvorufula) have been investigated. The diploid chromosome number was 2n = 56 (FN = 60). The mountain reedbuck karyotype consists of 26 acrocentric and two biarmed chromosome pairs resulting from two centric fusions involving chromosomes 2 and 25, and 6 and 10, respectively. In some animals, 57 chromosomes were detected. Variation in the diploid number was found to be due to polymorphism for the centric fusion 6;10. Both X and Y chromosomes are large and acrocentric. The entire Y chromosome and the proximal part of the X chromosome consist of heterochromatin. The chromosomes X, 9 and 14 appeared to be of caprine type. Chromosome aberrations have been detected in two of the 14 animals investigated. A de novo formed Robertsonian translocation rob(6;13) was found in one female heterozygous for the fusion 6;10. CBG-banding revealed one block of centromeric heterochromatin in the de novo formed translocation rob(6;13) and also in the evolutionarily fixed centric fusions 6;10 and 2;25. One examined male homozygous for fusion 6;10, had a mosaic 56,XY/57,XYY karyotype, with 11% of analyzed cells containing two Y chromosomes. The findings were confirmed by cross-species fluorescence in situ hybridization (FISH) with bovine (Bos taurus L.) chromosome painting probes. The study demonstrates the relevance of cytogenetic screening in captive animals from zoological gardens.

Cytotoxicity test and cytogenetic analysis of effects of aminoguanidine in vitro.

The potential genotoxic activity of chemical substances in vitro is usually assessed by the micronucleus test and by karyological analysis. Use of the fluorescent plus Giemsa (FPG) technique is also recommended in the event that positive results are found in the micronucleus test, or if there is an increased rate of structural and numerical chromosome aberrations compared with controls. The tested substance, aminoguanidine (AG), has a marked ability to inhibit the toxic effects of carbonyl products (carbonyl stress) that arise during the end-phases of non-enzymatic protein glycation both in vitro and in vivo. The importance of this ability follows the finding that the production of advanced glycation end-products (AGE) is a part of the molecular mechanism of the pathogenesis of chronic diabetic complications. The aim of this study was to test the cytotoxic and clastogenic effects of AG on cells of the diploid cell line B-HEF-2, derived from a three-month-old male fetus. The results of the test did not reveal any induction of micronucleus production in the analyzed cells at AG concentrations ranging between 1 x 10(-2) and 1 x 10(-4) mol.L-1. Karyological analysis showed no clastogenic effect of the tested substance nor any increased rate of structural chromosome aberrations. The positive properties of AG and to its potential use as a glycoxidation inhibitor and AGE production are somewhat dimmed by its ionic nature, which hampers hydrophobic interaction with the nonpolar components of biological membranes. For this reason, the authors will further study the cytotoxicity and cytogenetic analysis of Schiff bases of AG synthesis on the basis of natural aldehydes (resorcine aldehyde, pyridoxal, etc.) in which antiglycation activity has been detected.

Developmental defects and chromosomal aberrations in spontaneous abortions and stillbirths.

The authors analysed 1488 cases of spontaneous abortions and stillbirths in Bratislava. They focused on the course of human embryogenesis and the chromosomal constitution. A high mean frequency rate of both developmental defects (14.4%) and chromosomal aberrations (33.6%) was revealed and both were found to be in close relation with the length of gestation. The most severe developmental defects occurred mostly in early stages of human embryogenesis, i.e. in the 1st trimester of gestation.

[Pathologic karyotypes in autopsy material]. / Patologické karyotypy v súbore nekroptického materiálu.

In 1986-1989 the authors were concerned with the cultivation of necroptic material. Material was collected from five indication groups outlined in advance. A total of 231 specimens of necroptic material were cultivated, incl. 143 specimens subjected to cytological evaluation. From the above material 20 pathological karyotypes were diagnosed. The results of cytogenetic analysis of chromosome abnormalities were compared with the clinical and pathological diagnosis. Post-mortem chromosome analysis is important for elucidation of the aetiopathogenesis of perinatal deaths and for a comprehensive approach to families with genetic risk.

[Postmortem chromosome analysis and its significance]. / Postmortálna chromozómová analýza a jej význam.

Cultivation of necroptic material taken by pathologist or obstetrician according to determined indicative groups was performed during the years 1986-1990. Cytogenetical evaluation was feasible in 157 cultivated samples from the total of 252. There were found 32 pathological karyotypes among them.

[69, XXY triploidy in a liveborn infant]. / Triploidia 69, XXY u zivorodeného dietata.

Triploidy 69, XXY was described in a liveborn foetus weighing 760 g. Diagnosis was based on postmortal cytogenetical analysis.

[Experience with postmortem chromosome analysis]. / Skúsenosti s postmortálnou chromozómovou analýzou.

Over the years 1986-1988 necroptic material, collected according to 5 established indication groups, was cultured. A total of 202 samples of necroptic material cultured and 122 of these samples were analyzed cytogenetically. Seventeen pathologic karyotypes were diagnosed in the material, namely 7 cases of Down's syndrome, 2 cases of Klinefelter's syndrome, 2 cases of D/D translocation, 1 case of Turner's syndrome, 1 case of gonosomal mosaicism, and 1 case of Patau's syndrome.